Lyophilization, or freeze-drying, is a process widely used in the pharmaceutical industry for the preservation of biological and pharmaceutical materials. In lyophilization, water present in a material is converted to ice during a freezing step and then removed from the material by direct sublimation under low-pressure conditions during a primary drying step. During freezing, however, not all of the water is transformed to ice. Some portion of the water is trapped in a matrix of solids containing, for example, formulation components and/or the active ingredient. The excess bound water within the matrix can be reduced to a desired level of residual moisture during a secondary drying step. All lyophilization steps, freezing, primary drying and secondary drying, are determinative of the final product properties.
However, primary drying is typically the longest step in a lyophilization process. Therefore, optimization of this portion of the process has significant economic effect (Pikal et al. “Freeze-drying of proteins. Part 2: formulation selection,” BioPharm 3:26-30 (1990); Pikal et al. “The collapse temperature in freeze-drying: dependence of measurement methodology and rate of water removal from the glassy phase,” International Journal of Pharmaceutics, 62 (1990), 165-186). For many years, cycle and formulation optimization was performed to assure that the product temperature during primary drying would never exceed the collapse temperature. The collapse temperature is the product temperature during freeze-drying above which product cake begins to lose its original structure. It was reported in literature that, above the collapse temperature, product could experience slow sporadic bubbling, swelling, foaming, cavitation, fenestration, gross collapse, retraction and beading that may have consequences on the appearance of the product (MacKenzie, “Collapse during freeze-drying-Qualitative and quantitative aspects” In Freeze-Drying and Advanced Food Technology; Goldblith, S. A., Rey. L, Rothmayr, W. W., Eds.; Academic Press, New York, 1974, 277-307). As a result, it is thought that collapse results in poor product stability, long drying times (due to pore's collapse), uneven drying and loss of texture (R. Bellows, et al. “Freeze-drying of aqueous solutions: maximum allowable operating temperature,” Cryobiology, 9, 559-561 (1972). For proteins, collapse during freeze-drying has been reported to lead to elevated moisture, increased degradation rate and reconstitution time (Carpenter, J. F. et al. “Rational design of stable lyophilized protein formulations: some practical advice,” Pharmaceutical Research (1997), 14(8):969-975; Adams et al. “Optimizing the lyophilization cycle and the consequences of collapse on the pharmaceutical acceptability of Erwinia L-Asparaginase,” J. of Pharmaceutical Sciences, Vol. 8606, No. 12, December (1996); S. Passot et al. “Effect of product temperature during primary drying on the long-term stability of lyophilized proteins,” Pharm. Dev. and Tech., 12:543-553, 2007). Therefore, for many years, it was considered critical to freeze-dry under the collapse temperature.